Genetic Variant NOS1:p.Ile734Ile (chr12-117263909-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_000620.5(NOS1):c.2202T>C(p.Ile734Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 1,612,974 control chromosomes in the GnomAD database, including 412,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.75 ( 43283 hom., cov: 29)

Exomes 𝑓: 0.71 ( 368824 hom. )

Consequence

NOS1
NM_000620.5 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.374

Publications

43 publications found

Variant links:

Genes affected

NOS1 (HGNC:7872): (nitric oxide synthase 1) The protein encoded by this gene belongs to the family of nitric oxide synthases, which synthesize nitric oxide from L-arginine. Nitric oxide is a reactive free radical, which acts as a biologic mediator in several processes, including neurotransmission, and antimicrobial and antitumoral activities. In the brain and peripheral nervous system, nitric oxide displays many properties of a neurotransmitter, and has been implicated in neurotoxicity associated with stroke and neurodegenerative diseases, neural regulation of smooth muscle, including peristalsis, and penile erection. This protein is ubiquitously expressed, with high level of expression in skeletal muscle. Multiple transcript variants that differ in the 5' UTR have been described for this gene but the full-length nature of these transcripts is not known. Additionally, alternatively spliced transcript variants encoding different isoforms (some testis-specific) have been found for this gene.[provided by RefSeq, Feb 2011]

NOS1 Gene-Disease associations (from GenCC):

idiopathic achalasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NOS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 12-117263909-A-G is Benign according to our data. Variant chr12-117263909-A-G is described in ClinVar as Benign. ClinVar VariationId is 3060480.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-0.374 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000620.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NOS1	NM_000620.5	MANE Select	c.2202T>C	p.Ile734Ile	synonymous	Exon 13 of 29	NP_000611.1
NOS1	NM_001204218.2		c.2202T>C	p.Ile734Ile	synonymous	Exon 13 of 30	NP_001191147.1
NOS1	NM_001204213.2		c.1194T>C	p.Ile398Ile	synonymous	Exon 12 of 28	NP_001191142.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NOS1	ENST00000317775.11	TSL:1 MANE Select	c.2202T>C	p.Ile734Ile	synonymous	Exon 13 of 29	ENSP00000320758.6
NOS1	ENST00000338101.8	TSL:5	c.2202T>C	p.Ile734Ile	synonymous	Exon 12 of 29	ENSP00000337459.4
NOS1	ENST00000618760.4	TSL:5	c.2202T>C	p.Ile734Ile	synonymous	Exon 13 of 30	ENSP00000477999.1

Frequencies

GnomAD3 genomes

AF:

0.747

AC:

113472

AN:

151836

Hom.:

43234

Cov.:

show subpopulations

Gnomad AFR

AF:

0.886

Gnomad AMI

AF:

0.704

Gnomad AMR

AF:

0.550

Gnomad ASJ

AF:

0.769

Gnomad EAS

AF:

0.776

Gnomad SAS

AF:

0.739

Gnomad FIN

AF:

0.711

Gnomad MID

AF:

0.731

Gnomad NFE

AF:

0.711

Gnomad OTH

AF:

0.739

GnomAD2 exomes

AF:

0.689

AC:

171864

AN:

249378

AF XY:

0.698

show subpopulations

Gnomad AFR exome

AF:

0.888

Gnomad AMR exome

AF:

0.419

Gnomad ASJ exome

AF:

0.769

Gnomad EAS exome

AF:

0.765

Gnomad FIN exome

AF:

0.700

Gnomad NFE exome

AF:

0.712

Gnomad OTH exome

AF:

0.709

GnomAD4 exome

AF:

0.708

AC:

1033677

AN:

1461020

Hom.:

368824

Cov.:

AF XY:

0.709

AC XY:

515613

AN XY:

726866

show subpopulations

African (AFR)

AF:

0.892

AC:

29851

AN:

33472

American (AMR)

AF:

0.437

AC:

19535

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.761

AC:

19878

AN:

26118

East Asian (EAS)

AF:

0.783

AC:

31073

AN:

39680

South Asian (SAS)

AF:

0.732

AC:

63109

AN:

86222

European-Finnish (FIN)

AF:

0.695

AC:

37116

AN:

53376

Middle Eastern (MID)

AF:

0.733

AC:

4228

AN:

5766

European-Non Finnish (NFE)

AF:

0.707

AC:

785460

AN:

1111334

Other (OTH)

AF:

0.720

AC:

43427

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

13875

27751

41626

55502

69377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19724

39448

59172

78896

98620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.747

AC:

113570

AN:

151954

Hom.:

43283

Cov.:

AF XY:

0.742

AC XY:

55127

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.886

AC:

36747

AN:

41460

American (AMR)

AF:

0.549

AC:

8382

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.769

AC:

2666

AN:

3468

East Asian (EAS)

AF:

0.777

AC:

3995

AN:

5142

South Asian (SAS)

AF:

0.739

AC:

3548

AN:

4804

European-Finnish (FIN)

AF:

0.711

AC:

7500

AN:

10550

Middle Eastern (MID)

AF:

0.738

AC:

217

AN:

294

European-Non Finnish (NFE)

AF:

0.711

AC:

48320

AN:

67966

Other (OTH)

AF:

0.738

AC:

1553

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1375

2750

4126

5501

6876

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

844

1688

2532

3376

4220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.712

Hom.:

76720

Bravo

AF:

0.740

Asia WGS

AF:

0.735

AC:

2555

AN:

3478

EpiCase

AF:

0.712

EpiControl

AF:

0.719

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NOS1-related disorder

Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.8

(source)

DANN

Benign

0.68

PhyloP100

-0.37

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over